Activating the DNA Damage Response and Suppressing Innate Immunity: Human Papillomaviruses Walk the Line.

Claire D James,Molly L Bristol,Dipon Das,Iain M Morgan

doi:10.3390/pathogens9060467

Claire D James, Molly L Bristol + Show 2 more

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https://doi.org/10.3390/pathogens9060467

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Abstract

Activation of the DNA damage response (DDR) by external agents can result in DNA fragments entering the cytoplasm and activating innate immune signaling pathways, including the stimulator of interferon genes (STING) pathway. The consequences of this activation can result in alterations in the cell cycle including the induction of cellular senescence, as well as boost the adaptive immune response following interferon production. Human papillomaviruses (HPV) are the causative agents in a host of human cancers including cervical and oropharyngeal; HPV are responsible for around 5% of all cancers. During infection, HPV replication activates the DDR in order to promote the viral life cycle. A striking feature of HPV-infected cells is their ability to continue to proliferate in the presence of an active DDR. Simultaneously, HPV suppress the innate immune response using a number of different mechanisms. The activation of the DDR and suppression of the innate immune response are essential for the progression of the viral life cycle. Here, we describe the mechanisms HPV use to turn on the DDR, while simultaneously suppressing the innate immune response. Pushing HPV from this fine line and tipping the balance towards activation of the innate immune response would be therapeutically beneficial.

Highlights

Human papillomaviruses activate the DNA damage response and suppress innate immunity, two processes that are required for a successful viral life cycle [1,2,3,4,5,6]
This review summarizes our understanding of the Human papillomaviruses (HPV) components regulating the DNA damage response (DDR) and Innate Immune Response (IIR)
Our recent demonstration that HPV16 genomes activate the DDR independently from E6 and E7 expression demonstrates that viral replication likely contributes to activation of the DDR

Summary

Introduction

Human papillomaviruses activate the DNA damage response and suppress innate immunity, two processes that are required for a successful viral life cycle [1,2,3,4,5,6]. There is a link between these two pathways in non-HPV cells; DNA damage can induce the innate immune response, resulting in interferon production and potential attenuation of cellular proliferation [7,8,9,10,11,12]. This replication stress could result in the production of DNA fragments that could egress to the cytoplasm and activate the innate immune response (Figure 2). Inhibition of the DDR blocks the HPV life cycle and is a strategy for controlling infection and treating cancers

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